Retroviral brain disease induced by murine polytropic retroviruses related to Fr98 was associated with upregulation of several chemokines and cytokines including MCP-1, MIP1a, MIP1b, RANTES, TNFa and IP-10. Following intraventricular inoculation of neural stem cells infected with several polytropic retroviruses, very high virus levels were induced in brain. Subsequently increased levels of the above cytokines and chemokines were detected in association with clinical neurological disease. Astrocytes were shown to be the main source of production of MCP-1, and microglia were the main producers of MIP1a and MIP1b. Neural stem cells infected with ecotropic retroviruses failed to induce upregulation of cytokines and chemokines or neurological disease, in spite of the presence of high virus levels. Thus viral envelope sequences important in tropism and receptor specificity appeared to strongly influence the induction of this disease. Furthermore, interactions between astroglia and microglia producing different proinflammatory cytokines and chemokines appeared to be part of the pathogenic process.